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United States Patent | 5,034,386 |
Peck ,   et al. | * July 23, 1991 |
This invention provides compositions comprising a physiologically-active agent and a compound having the structural formula ##STR1## wherein each X, Y and Z may represent oxygen, sulfur or two hydrogen atoms, provided however that, when Z represents two hydrogen atoms, both X and Y represent oxygen or sulfur and when Z represents oxygen or sulfur at least one of X and Y must represent oxygen or sulfur; m is 2-6; R' is H or a lower alkyl group having 1-4 carbon atoms; n is 0-17 and R is --CH.sub.3, ##STR2## wherein R" is H or halogen in an amount effective to enhance the penetration of the physiologically-active agent through the skin or other membrane of the body of an animal.
Inventors: | Peck; James V. (Costa Mesa, CA); Minaskanian; Gevork (Irvine, CA) |
Assignee: | Whitby Research, Inc. (Richmond, VA) |
[*] Notice: | The portion of the term of this patent subsequent to December 12, 2006 has been disclaimed. |
Appl. No.: | 233553 |
Filed: | August 17, 1988 |
Current U.S. Class: | 514/212.03; 514/212.08; 514/946; 514/947 |
Intern'l Class: | A61K 031/55 |
Field of Search: | 514/212,946,947 |
3051616 | Aug., 1962 | Drapal | 167/37. |
3085931 | Apr., 1963 | Darlington | 167/37. |
3157641 | Feb., 1964 | Wallis et al. | 260/239. |
3306910 | Feb., 1967 | Louthan | 260/326. |
3306911 | Feb., 1967 | Doss | 260/326. |
3332938 | Jul., 1967 | Mayhew et al. | 260/239. |
3342673 | Sep., 1967 | Kaufman et al. | 167/42. |
3551544 | Dec., 1970 | Herschler | 424/7. |
3598122 | Aug., 1971 | Zaffaroni | 128/155. |
3598123 | Aug., 1971 | Zaffaroni | 128/155. |
3678156 | Jul., 1972 | MacMillan et al. | 424/68. |
3731683 | May., 1973 | Zaffaroni | 128/155. |
3742951 | Jun., 1973 | Zaffaroni | 128/155. |
3814097 | Jun., 1974 | Ganderton et al. | 128/268. |
3823152 | Jul., 1974 | Morimoto | 260/293. |
3865814 | Feb., 1975 | Lussi et al. | 260/239. |
3891757 | Jun., 1975 | Higuchi | 424/343. |
3921636 | Nov., 1975 | Zaffaroni | 128/2. |
3954966 | May., 1976 | Lim et al. | 424/78. |
3960922 | Jun., 1976 | Baker et al. | 260/465. |
3966806 | Jun., 1976 | Baker et al. | 260/558. |
3972995 | Aug., 1976 | Tsuk et al. | 424/28. |
3989815 | Nov., 1976 | Rajadhyaksha | 424/60. |
3989816 | Nov., 1976 | Rajadhyaksha | 424/60. |
3991203 | Nov., 1976 | Rajadhyaksha | 424/59. |
3993072 | Nov., 1976 | Zaffaroni | 128/260. |
3993073 | Nov., 1976 | Zaffaroni | 128/260. |
3996934 | Dec., 1976 | Zaffaroni | 128/268. |
4021224 | May., 1977 | Pallos et al. | 71/88. |
4031894 | Jun., 1977 | Urfahart. | |
4060084 | Nov., 1977 | Chandrasekoran et al. | 128/260. |
4069307 | Jan., 1978 | Higuchi. | |
4077407 | Mar., 1978 | Theeumes. | |
4118500 | Oct., 1978 | Pritzlaff et al. | |
4122170 | Oct., 1978 | Rajadhyaksha | 424/180. |
4201211 | May., 1980 | Chandrasekoran et al. | |
4264594 | Apr., 1981 | McGonim et al. | |
4284648 | Aug., 1981 | Hussain et al. | |
4292299 | Sep., 1981 | Sajuki. | |
4311481 | Jan., 1982 | Matelne | 424/180. |
4316893 | Feb., 1982 | Rajadhyaksha | 424/180. |
4405616 | Sep., 1983 | Rajadhyaksha | 424/244. |
4415563 | Nov., 1983 | Rajadhyaksha | 424/180. |
4423040 | Mar., 1983 | Rajadhyaksha | 424/185. |
4424210 | Jan., 1984 | Rajadhyaksha | 424/155. |
4525199 | Jun., 1985 | Rajadhyaksha | 514/788. |
4537776 | Aug., 1985 | Cooper | 514/557. |
4552872 | Nov., 1985 | Cooper | 514/557. |
4557934 | Dec., 1985 | Cooper | 424/155. |
Foreign Patent Documents | |||
947764 | May., 1974 | CA. | |
29617 | Jun., 1981 | EP. | |
29618 | Jun., 1981 | EP. | |
010437 | Mar., 1984 | EP. | |
129284 | Dec., 1984 | EP. | |
164998 | Dec., 1985 | EP. | |
2003128 | Jul., 1971 | DE. | |
1243632 | Sep., 1960 | FR | 540/525. |
45-22121 | Jul., 1970 | JP. | |
56-020572 | Feb., 1981 | JP. | |
61-033128 | Feb., 1986 | JP. | |
61-129140 | Jun., 1986 | JP. | |
549688 | Mar., 1986 | ES. | |
528848 | Nov., 1977 | SU | 548/519. |
1102521 | Feb., 1968 | GB | 540/525. |
1421743 | Jan., 1976 | GB. | |
1427744 | Jan., 1976 | GB. | |
2078725 | Jan., 1982 | GB | 548/530. |
Current Therapy, p. 662 (1981). Current Therapy, pp. 599-603 (1984). Barry et al., Proc. Royal Irish Academy, vol. 55, pp. 137-148 (1953)--see p. 146*. Kometani, et al., "A Synthesis of Succinimides and Glutarimides From Cyclic Anhydrides," Chem. Abs., 106:84339k (1986). Tremol Lozano, "Process for the Preparation of Benzoylpyrrolidinones," Chem. Abs., 106:6713m (1986). Betrakova, et al., "Synthesis of Alkylene Diglutarimides," 69:86313p, (1968). Chemical Abstracts 82:93905e. Chemical Abstracts 83:1758d. Chemical Abstracts 83:91780g. Chemical Abstracts 102:183860x. Chemical Abstracts 104:213242h. Bennett, S. L., et al, "Optimization of Bioavailability or Topical Steroids: Non-Occluded Penetration Enhancers Under Thermodynamic Control," J. Pharm Pharmcol. 37(5), 298-304, 1985. Goldman, L., et al., "Preliminary Investigative Studies with DDT in Dermatologic and Plastic Surgery", Lasers Surg Med 5(5): 453-456, 1985. Chow, DS-L, et al., "Consentration-Dependent Enhancement of 1-Dodecylazacyloheptan-2-One on the Percutaneous Penetration Kinetics of Triamcinolone Acetonide", J. Pharm Sci 73(12):1794-1799, 1984. DeClercq, E., "Topical Treatment of Cutaneous Herpes Simplex Virus Infection in Hairless Mice with (E)-5-(2-Bromovinyl)-2'-Dioxyurdine and Related Compounds", Antimicrob Agents Chemother 26(2): 155-159, 1984. Goodman, M., et al., Differential Scanning Colorimetry (DSC) of Human Stratum Corneum: Effect of Azone. Presentation at the British Pharmaceutical Conference Leeds, 1985. Hadgraft, J., et al., "Facilitated Transport of Sodium Salicylate Across an Artificial Lipid Membrane by Azone", J. Pharm Pharmacol 37(10): 725-727, 1985. Higuchi, W. I., "Macro- and Micro-Physical Chemical Considerations in Understanding Drug Transport in the Stratum Corneum", Second Int'l Symp. Recent Advances in Drug Delivery Systems, Salt Lake City, Utah, 1985. Higuchi, W. I., et al., "Topical Delivery of Antiviral Agents: In Vivo/In Vitro Correlations", Proc. Int. Symp., pp. 1-7, 1984. Hoelgaard A., "Dermal Drug Delivery--Improvement by Choice of Vehicle or Drug Derivative", 2nd Int'l Symp Recent Adv Drug Delivery Systems, 1985. Liang, W. Q., et al., "Affect of Azone on Local Pharmacokinetics of Para-Aminobenzoic Acid in Skin", 11th Int'l Symp. Controlled Release Bioactive Mat., 1984. Maibach, H. I., et al., "Phototoxicity (Photoirritation) of Topical and Systemic Agents", Advances in Modern Toxicology, 4:211-223, 1977. Marzulli, F. N., et al., Contact Allergy: Predictive Testing in Humans, Advances in Modern Toxicology 4:253-372, 1977. McCullough, J. L. et al., "Regulation of Epidermal Prolifieration in Mouse Epidermis by Combination of Difluoromethyl Ornithine (DFMO) and Methylglyoxal Bis (Guancylhydrazone) (MGBG)", J. Invest. Dermatol. 85(6): 518-521, 1985. McCullough, J. L., et al., "Development of a Topical Hematoporphysin Derivative Formulation: Characterization of Photosensitizing Effects". In Vivo., J. Invest Dermatol 81(6): 528-532, 1983. Ohshima, T. et al., "Enhancing Effect of Absorption Promoters on Percutaneous Absorption of a Model Dye (6-Carboxyfluorescein) as Poorly Absorbable Drugs. III. Study on the Absorption Promoting Effect of Azone", J. Pharm. Dyn 8:900-905, 1985. Ryatt, J. K., "Pharmacodynamic Measurement of Percutaneous Penetration Enhancement In Vivo", J. Pharm Sci 75:(4), 374-377, 1986. Stoughton, R. B., "Azone as a Promoter of Percutaneous Absorption", (1983), Acta Pharm 20(1):62. Shannon, W. M., et al., "Influence of 1-Dodecylazacydoheptan-2-one (Azone) on the Topical Therapy of Cutaneous Herpes Simplex Virus Type 1 Infection in Hairless Mice with 2',3'-D-Arabinofuranosyladenine", J Pharm Sci 74(11):1157-1161, 1985. Spruance, S. I., et al., "Effect of Azone and Propylene Glycol on Penetration of Trifluorothymidine Through Skin and Efficacy of Different Topical Formulations Against Cutaneous Herpes Simplex Virus Infections in Guinea Pigs", Antimicrob Agent Chemother 25(5): 819-823, 1984. Stoughton, R. B., et al., "Azone.RTM.: A New Non-Toxic Enhancer of Cutaneous Penetration", Drug. Dev. Ind. Pharm 9(4): 725-744, 1983. Stoughton, R. B., "Azone Enhances Percutaneous Penetration", IN: Psoriasis Proceedings of the Third Int'l Sump., 397-8, 1982. Stoughton, R. B., "Enhanced Percutaneous Penetration with 1-Dodecylazacycloheptan-2-one", Archives of Derm 118:474-477, 1982. Sugibayashi, K., et al., "Effect of the Absorption Enhancer, Azone, on the Transport of 4-Fluorourcil Across Hairless Rat Skin", J. Pharm Pharm 37(8):578-580, 1985. Toutitou, E., et al., "Effect of Propylene Glycol, Azone and N-Decylmethyl Suphoxide on Skin Permeation Kinetice of 5-Fluorouracil," Int. J. Pharm 1(27):89-98, 1985. Wooton, P. K., et al., "Vehicle Effect on Topical Drug Delivery. III. Effect of Azone on the Cutaneous Permeation of Metronidazole and Propylene Glycol", Int J Pharm 1(24): 19-26, 1985. Rajadkyaksha, V., et al., "Transdermal Delivery of ISDN from Hercon Patches Containing Azone", Proceed Intern Symp Control Rel Biact Mater, 12 (222-323), 1985. Zoler, M. L., "Skin Penetration of Antiherpes Drugs Can Be Enhanced by Azone", Dermatology Times 5(2), 1984. Hadgraft, J., "Percutaneous Absorption", Cos & Toiletries 100, 32-28, 1985. Mehr, A. Z., "Evaluation of Commercial and Experimental Repellents Against Xenopsylla Cheopis (Siphonaptera: Pulicidae)", J. Med. Entomol, vol. 21, No. 6: 665-669. Skinner, W. A., et al., "Tick Repellents II: N-Substituted Azacyclopentanones and Azacyclopentenones", J Pharm Sci 72(11):1354, 1983. Vaidyanathan, R., et al., "Dodecylazacycloheptan-2-One (Azone.RTM.) Enhanced Delivery of Drugs into the Epidermis I: Effect of Enhancer Concentration on the Permeability of Select Compounds." Abstract No. 97, Pharm Sci 12(2): 126, 1982. Vaidyanathan, R., et al., "Dodecylazacycloheptan-2-One (Azone.RTM.) Enhanced II: Permeation of Ara-A-5'-Valerate Through Hairless Mouse Skin From Prototype Formulations", Abstract No. 98, Pharm Sci 12(2): 126, 1982. |
TABLE ______________________________________ Penetration-Enhancing Percent Penetration Agent 6 hr. 24 hr. ______________________________________ Example 1 18.96 74.34 1-n-Dodecylcycloheptan-2-one 16.64 60.94 Ethanol (only) 0.56 6.78 Ethanol (only, repeat) 0.5 5.64 ______________________________________
______________________________________ Solution (%) ______________________________________ Griseofulvin 1 1-n-Dodecanoylazacycloheptan-2-one 1 Isopropyl myristate 5 Fragrance 0.1 Ethanol 92.9 ______________________________________
______________________________________ Formulation 25% Freon.sup.1 75% ______________________________________ .sup.1 Freon is 75/25 Freon 114/12.
______________________________________ % ______________________________________ Clindamycin base 1.0 Stearyl alcohol, U.S.P. 12.0 Ethoxylated cholesterol 0.4 Synthetic spermaceti 7.5 Sorbitan monooleate 1.0 Polysorbate 80, U.S.P. 3.0 1-n-Dodecanoylazacycloheptan-2-one 0.5 Sorbitol solution, U.S.P. 5.5 Sodium citrate 0.5 Chemoderm #844 Fragrance 0.2 Purified water 68.4 ______________________________________
______________________________________ A (%) B (%) ______________________________________ Clindamycin base -- 1.0 Clindamycin phosphate acid 1.3 -- Sodium hydroxide 0.077 -- 1.0M Hydrochloric acid -- 2.27 Disodium edetate:2H.sub.2 O 0.003 0.003 Fragrances 0.5 0.5 1-n-Dodecanoylazacycloheptan-2-one 1.0 1.0 Purified water 20.0 17.73 Isopropanol 77.12 77.497 ______________________________________
______________________________________ % ______________________________________ Neomycin sulfate 0.5 Lidocaine 0.5 Hydrocortisone 0.25 1-n-Dodecanoylazacycloheptan-2-one 0.5 Propylene glycol 98.25 ______________________________________
______________________________________ % ______________________________________ p-aminobenzoic acid 2.0 Benzyl alcohol 0.5 1-n-Dodecanoylazacycloheptan-2-one 1.0 Polyethylene glycol 500-MS 10.0 Isopropyl lanolate 3.0 Lantrol 1.0 Acetylated lanolin 0.5 Isopropyl myristate 5.0 Light mineral oil 8.0 Cetyl alcohol 1.0 Veegum 1.0 Propylene glycol 3.0 Purified water 64.0 ______________________________________
______________________________________ % ______________________________________ 5-Fluorouracil 5.0 1-n-Dodecanoylazacycloheptan-2-one 0.1 Polyethylene glycol 5.0 Purified water 89.9 ______________________________________
______________________________________ % ______________________________________ Diethyltoluamide 0.1 1-n-Dodecanoylazacycloheptan-2-one 0.1 Ethanol 99.8 ______________________________________
______________________________________ % ______________________________________ Fluocinolone acetonide 0.001-1 Cetyl alcohol 15.0 Propylene glycol 10.0 Sodium lauryl sulfate 15.0 1-n-Dodecanoylazacycloheptan-2-one 1.0 Water (to make 100%) ______________________________________